2-substituted ergolines useful as neuroleptics and antidepressants

ABSTRACT

Novel ergoline derivatives, substituted in the 2-position, of the formula ##STR1## wherein C 8  -C 9  and C 9  -C 10  each independently is a CC-single or a C═C-double bond, but not together a cumulated double bond, and the substituent in the 8-position is in the α- or β-configuration where C 8  -C 9  is a CC-single bond, 
     R 2  is 
     CN, SR, SOR, ##STR2##  wherein n is 2 or 3, ##STR3##  and --CH(OH)R, wherein R has the meaning of H or C 1-4  -alkyl, the grouping COR&#39; and CSR&#39; wherein R&#39;═OH, OC 1-4  -alkyl, benzyl, NH 2  or NHR&#34;, 
     the grouping CH═CH--CO 2  R&#34; and CH 2  --CH 2  --CO 2  R&#34; wherein R&#34;═C 1-4  -alkyl, 
     the grouping C|C-R&#39;&#34; and HC═CH--R&#39;&#34; wherein R&#39;&#34;═ hydrogen, C 1-4  -alkyl, phenyl, CH 2  OH, CR&#34; 2  OH, ##STR4##  CO 2  R&#34;, CH 2  NR&#34; 2  or SiMe 2  R&#34;; C 1-3  -alkyl, or C 1-3  -alkyl substituted by OH or phenyl; or ##STR5##  wherein R&#34; is C 1-4  alkyl, R 6  is C 1-4  -alkyl and 
     R 8  is methyl, NH--CO--NEt 2  or NH--CS--NEt 2 , 
     and the physiologically acceptable acid addition salt thereof, possess biological efficacy in the region of the central nervous system, e.g., as neuroleptics and anti-depressants.

The present invention relates to novel ergoline derivatives of Formula Iwhich are substituted in the 2-position, their preparation according tomethods known per se, and their use as medicinal agents based on thesecompounds.

SUMMARY OF THE INVENTION

It is an object of this invention to provide new substituted ergolinylcompounds having valuable pharmacological properties and areintermediates for the preparation of the same and of each other.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

These objects have been attained by providing new, substituted ergolinesof Formula I ##STR6## wherein C₈ - - - C₉ and C₉ - - - C₁₀ eachindependently is a CC-single or a C═C-double bond, but not together acumulated double bond, and the substituent in the 8-position is in theα- or β-configuration where C₈ - - - C₉ is a CC-single bond,

R² is

CN, SR, SOR, ##STR7## or --CH(OH)R wherein R is H or C₁₋₄ -alkyl and nis 2 or 3; the grouping COR' or CSR', wherein R'═OH, OC₁₋₄ -alkyl,benzyl, NH₂ or NHR";

the grouping CH═CH--CO₂ R" or CH₂ --CH₂ --CO₂ R" wherein R"═C₁₋₄ -alkylthroughout the above;

the grouping C.tbd.C--R'" and HC═CH--R'" wherein R'"═hydrogen, C₁₋₄-alkyl, phenyl, CH₂ OH, CR"₂ OH, ##STR8## CO₂ R", CH₂ NR"₂ or SiMe₂ R";C₁₋₃ -alkyl, or C₁₋₃ -alkyl substituted by OH or phenyl, or ##STR9##wherein R" is C₁₋₄ -alkyl; R⁶ is C₁₋₄ -alkyl and

R⁸ is methyl or the grouping NH--CO--NEt₂ or NH--CS--NEt₂,

and physiologically acceptable salts thereof.

DETAILED DISCUSSION

The salts of the compounds of Formula I according to this inventioninclude acid addition salts and are derived from physiologicallyacceptable acids. Such physiologically acceptable acids are inorganicacids, e.g., hydrochloric acid, nitric acid, phosphoric acid, sulfuricacid, hydrobromic acid, hydriodic acid, nitrous acid or phosphorousacid, or organic acids, such as, for example, aliphatic mono- ordi-carboxylic acids, phenyl-substituted alkanecarboxylic acids,hydroxyalkanecarboxylic acids, or alkanedicarboxylic acids, aromaticacids or aliphatic or aromatic sulfonic acids. Examples forphysiologically acceptable salts of these acids include, therefore, thesulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogen phosphate, dihydrogen phosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caproate,heptanoate, propiolate, malonate, succinate, suberate, sebacate,fumarate, maleate, mandelate, butyne-1,4-dioate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, terephthalate,benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, -hydroxy-butyrate, glycollate, malate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate ornaphthalene-2-sulfonate.

Alkyl residues of up to 3 or 4 carbon atoms throughout the foregoinginclude those derived from aliphatic hydrocarbons, for example, methyl,ethyl, n-propyl, isopropyl and n-butyl, isobutyl, test-butyl, etc.

As compared with conventional ergolines unsubstituted in the 2-position,for example, lisuride or terguride, the compounds of Formula I accordingto this invention are distinguished by a centrally dopaminergic and/orα₂ -receptor-blocking activity.

The central α₂ -receptor blockage, for example, of1,1-diethyl-3-(6-methyl-2-methylthio-8α-ergolinyl)urea (A) and of1,1-diethyl(6-methyl-2-ethynyl-8α-ergolinyl)urea (B) was illustrated inan interaction test with the α₂ -receptor agonist clonidine on miceafter a one-time i.p. pretreatment (parameter" elimination ofhypothermia caused by clonidine 0.1 mg/kg i.p.). Male NMRI mice werepretreated with various doses of A and B, respectively, which themselvesdo not affect the thermoregulation of the test animals, and with acarrier medium, respectively. After 30 minutes all animals receivedclonidine 0.1 mg/kg i.p. Rectal temperature was measured with the aid ofa thermal probe 60 minutes after administration of A or B, or of carriermedium (=30 minutes after clonidine). The mice pretreated with carriermedium exhibited hypothermia. The effect of clonidine, that of loweringbody temperature, was significantly reduced or eliminated incorrellation with the dose of animals pretreated with compound A or Baccording to this invention. The clonidine-antagonistic effects of A andof B were statistically significant in a dose as low as 0.2 mg/kg. SeeTable 1.

Central dopamine receptor blockage of A and B was demonstrated in aninteraction test with the dopamine receptor agonist apomorphine in miceafter a one-time pretreatment i.p. The test involved elimination ofhypothermia caused by apomorphine 5 ng/kg i.p. Male NMRI mice werepretreated with various doses of A and B which themselves do not affectthermoregulation of the test animals, and, respectively, with a carriermedium. Thirty minutes later, all animals received apomorphine 5 mg/kgi.p. Rectal temperature was measured with the aid of a thermal probe 60minutes after administration of A or B, or of carrier medium (=30minutes after apomorphine). While the mice pretreated with carriermedium showed hypothermia, the effect of apomorphine of lowering bodytemperature was significantly reduced in correlation with the dose inanimals pretreated with A or B. The apomorphine-antagonistic effects ofA and of B were statistically significant in a dose as low as 0.2 mg/kg.See Table 2.

Based on these findings, the compounds of this invention can thus beutilized as neuroleptics for the treatment of psychoses of theschizophrenic array of symptoms or as antidepressants.

In order to use the compounds of this invention as medicinal agents,they are made into pharmaceutical preparations containing, in additionto the active ingredient, pharmaceutical, organic or inorganic, inertexcipients suitable for enteral or parenteral administration. Theseinclude, for example, water, gelatin, gum arabic, lactose, amylose,magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. Thepharmaceutical preparations can be present in the solid form, e.g., astablets, dragees, suppositories, capsules, or in the liquid for, forexample as solutions, suspensions or emulsions. If desired, they maycontain auxiliary agents, such as preservatives, stabilizers, wettingagents or emulsifiers, salts for varying the osmotic pressure, orbuffers.

The pharmacologically active compounds of this invention can beprocessed in accordance with conventional methods of galenic pharmacy toproduce for administration to patients, e.g., mammals including humans.Conventional excipients are pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral, enteral or topicalapplication which do not deleteriously react with the active compounds.Suitable pharmaceutically acceptable carriers include but are notlimited to water, salt solutions, alcohols, gum arabic, vegetable oils,polyethylene glycols, gelatine, lactose, amylose, magnesium stearate,talc, silicic acid, viscous paraffin, perfume oil, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxy-methylcellulose, polyvinyl pyrrolidone, etc. The pharmaceuticalpreparations can be sterilized and if desired mixed with auxiliaryagents, e.g., lubricants, preservatives, stabilizers, wetting agents,emulsifiers, salts for influencing osmotic pressure, buffers, coloring,flavoring and/or aromatic substances and the like which do notdeleteriously react with the active compounds.

For parenteral application, particularly suitable are injectable sterilesolutions, preferably oil or aqueous solutions, as well as suspensions,emulsions, or implants, including suppositories. Ampoules are convenientunit dosages.

For enteral application, particularly suitable are tablets, dragees,suppositories or capsules having talc and/or a carbohydrate carrier orbinder or the like, the carrier preferably being lactose and/or cornstarch and/or potato starch. A syrup, elixir or the like can be usedwherein a sweetened vehicle is employed. Sustained release compositionscan be formulated including those wherein the active compound isprotected with differentially degradable coatings, e.g., bymicroencapsulation, multiple coatings, etc.

Generally, the compounds of this invention are dispensed in unit dosageform comprising 0.5-5 mg. In a pharmaceutically acceptable carrier perunit dosage.

The dosage of the compounds according to this invention generally is0.5-20 mg/kg/day when administered to patients, e.g., humans as aneuroleptic analogously to the known agent haloperidol, and is 0.5-20mg/kg/day when administered as an antidepressant analogously to theknown agent mianserin.

Dosages for a given host can be determined using conventionalconsiderations, e.g., by customary comparison of the differentialactivities of the subject compound and of a known agent, e.g., by meansof an appropriate, conventional pharmacological protocol.

                                      TABLE 1                                     __________________________________________________________________________    Antagonistic effect of pretreatment (30 min. i.p.) with various doses of      2-substituted ergoline ureas on hypothermia in mice triggered by              clonidine                                                                     (0.1 mg/kg i.p.). Rectal temperature of test animals was measured 30          min.                                                                          after clonidine (=60 min. after test compound)                                (*: p < 0.05, **: p <vs. control; variance analysis/Dunnett                   __________________________________________________________________________    test).                                                                                     Rectal Temperature [°C.] (Average Values ±                          S.E.M.)                                                                       Dose of Test Compound [mg/kg]                                    Compound   n Control                                                                             0.05  0.1   0.2     0.39                                   __________________________________________________________________________    TDHL       8 33.1 ± 0.2                                                                       --    --    --      33.6 ± 0.2                          2-C.tbd.CH--TDHL                                                                         8 34.6 ± 0.2                                                                       33.9 ± 0.2                                                                       34.5 ± 0.2                                                                       35.3 ± 0.2                                                                         35.6 ± 0.3*                         2-SCH.sub.3 --TDHL                                                                       8 33.6 ± 0.1                                                                       34.2 ± 0.1                                                                       34.2 ± 0.2                                                                        35.4 ± 0.3**                                                                       35.3 ± 0.1**                       2-CH.sub.3 --TDHL                                                                        8 34.1 ± 0.2                                                                       --    --    34.3 ± 0.3                                                                         34.8 ± 0.2                          2-SC.sub.2 H.sub.5 --TDHL                                                                8 33.7 ± 0.2                                                                       --    34.4 ±  0.2                                                                      34.0 ± 0.3                                                                         34.9 ± 0.4*                         2-SCH(CH.sub.3).sub.2 --TDHL                                                             8 34.0 ± 0.2                                                                       --    34.0 ± 0.2                                                                       34.8 ± 0.2                                                                         34.6 ± 0.2                          2-SC.sub.3 H.sub.2 --TDHL                                                                8 33.7 ± 0.1                                                                       --    --    34.1 ± 0.2                                                                         34.4 ± 0.2*                         __________________________________________________________________________                 Rectal Temperature [°C.] (Average Values ±                          S.E.M.)                                                                       Dose of Test Compound [mg/kg]                                    Compound   n 0.78   1.56    3.13    6.26    12.5                              __________________________________________________________________________    TDHL       8 33.7 ± 0.3                                                                        34.1 ± 0.3**                                                                       34.7 ± 0.2**                                                                       34.8 ± 0.3**                                                                       --                                2-C.tbd.CH--TDHL                                                                         8 35.7 ± 0.3**                                                                      35.9 ± 0.2**                                                                       --      --      --                                2-SCH.sub.3 --TDHL                                                                       8 35.4 ± 0.2**                                                                      35.4 ± 0.3**                                                                       35.9 ± 0.3**                                                                       --      --                                2-CH.sub.3 --TDHL                                                                        8 35.2 ± 0.2**                                                                      36.0 ± 0.2**                                                                       35.9 ± 0.2**                                                                       --      --                                2-SC.sub.2 H.sub.5 --TDHL                                                                8 35.5 ± 0.6**                                                                      34.7 ± 0.5                                                                         35.9 ± 0.2**                                                                       --      --                                2-SCH(CH.sub. 3).sub.2 --TDHL                                                            8 35.3 ± 0.2**                                                                      36.2 ± 0.3**                                                                       37.0 ± 0.3**                                                                       --      --                                2-SC.sub.3 H.sub.2 --TDHL                                                                8 34.6 ± 0.2**                                                                      34.7 ± 0.2**                                                                       35.8 ± 0.1**                                                                       --      --                                __________________________________________________________________________     TDHL = 1.1 Diethyl(6-methyl-8ergolinyl)urea                              

                                      TABLE 2                                     __________________________________________________________________________    Antagonistic effect of pretreatment (30 min. i.p.) with various doses of      2-substituted ergoline ureas on hypothermia in mice triggered by              apomorphine                                                                   (5 mg/kg i.p.). Rectal temperature of test animals was measured 30 min.       after apomorphine (=60 min. after test compound)                              (*: p <0.05, **: p <0.01 vs. control; variance analysis/Dunnett               __________________________________________________________________________    test).                                                                                     Rectal Temperature [°C.] (Average Values ±                          S.E.M.)                                                                       Dose of Test Compound [mg/kg]                                    Compound   n Control 0.05  0.1   0.2     0.39                                 __________________________________________________________________________    TDHL       8  32.5 ± 0.4**                                                                      --    --    --      --                                   2-C.tbd.CH--TDHL                                                                         8 34.0 ± 0.3                                                                         33.6 ± 0.5                                                                       33.7 ± 0.5                                                                        36.1 ± 0.4**                                                                       36.6 ± 0.4**                     2-SCH.sub.3 --TDHL                                                                       8 32.9 ± 9.4                                                                         34.3 ± 0.5*                                                                      33.9 ± 0.3                                                                        34.7 ± 0.4**                                                                       35.8 ± 0.3**                     2-CH.sub.3 --TDHL                                                                        8 33.7 ± 0.5                                                                         --    --    33.0 ± 0.4                                                                         33.2 ± 0.3                        2-SC.sub.2 H.sub.5 --TDHL                                                                8 32.7 ± 0.3                                                                         --    33.3 ±  0.2                                                                      33.7 ± 0.4                                                                         34.1 ± 0.7                        2-SCH(CH.sub.3).sub.2 --TDHL                                                             8 33.1 ± 0.3                                                                         --    --    33.0 ± 0.3                                                                         33.0 ± 0.3                        2-SC.sub.3 H.sub.7 --TDHL                                                                8 33.0 ± 0.6                                                                         --    32.9 ± 0.3                                                                       33.1 ± 0.3                                                                         33.5 ± 0.6                        __________________________________________________________________________                 Rectal Temperature [°C.] (Average Values ±                          S.E.M.)                                                                       Dose of Test Compound [mg/kg]                                    Compound   n 0.78    1.56    3.13   6.25   12.5                               __________________________________________________________________________    TDHL       8 33.9 ± 0.5                                                                         33.8 ± 0.4                                                                         35.1 ± 0.5**                                                                      35.5 ± 0.5**                                                                      36.0 ± 0.                       2-C.tbd.CH--TDHL                                                                         8  37.3 ± 0.2**                                                                       36.7 ± 0.2**                                                                      35.7 ± 0.3**                                                                      --     --                                 2-SCH.sub.3 --TDHL                                                                       8  35.5 ± 0.2**                                                                       35.5 ± 0.3**                                                                      --     --     --                                 2-CH.sub.3 --TDHL                                                                        8 34.3 ± 0.3                                                                         34.1 ± 0.3                                                                         35.0 ± 0.2**                                                                      35.5 ± 0.2**                                                                      --                                 2-SC.sub.2 H.sub.5 --TDHL                                                                8  35.2 ± 0.5**                                                                       34.8 ± 0.4**                                                                      35.5 ± 0.4**                                                                      --     --                                 2-SCH(CH.sub.3).sub.2 --TDHL                                                             8 33.4 ± 0.5                                                                         34.3 ± 0.4                                                                         34.0 ± 0.4                                                                        34.2 ± 0.5                                                                        --                                 2-SC.sub.3 H.sub.7 --TDHL                                                                8 33.9 ± 0.5                                                                         33.9 ± 0.5                                                                         34.7 ± 0.6                                                                        --     --                                 __________________________________________________________________________     TDHL = 1.1 Diethyl(6-methyl-8ergolinyl)urea                              

The compounds of this invention of Formula I wherein R² is CN, SR, SOR,##STR10## and --C(HOH)R where R is C₁₋₄ -alkyl, can be prepared fromcompounds of Formula II ##STR11## according to conventional methodswherein C₈ - - - C₉, C₉ - - - C₁₀, R⁶ and R⁸ have the meanings indicatedin Formula I above, e.g., by reaction with an appropriate electrophilicreagent.

When the substituent R² represents the nitrile group, then the processis performed by adding chlorosulfonyl isocyanate to the ergoline ofFormula II in an inert solvent, such as acetonitrile ordimethylformamide, in the presence of a base, such as trimethyl- ortriethylamine (cf. DOS 2,365,974). The use of an inert gas atmosphere isadvantageous. The reaction is completed after 10-50 hours at roomtemperature.

Where the substituent R² represents the S-alkyl or S-methyl group, thenthe process is conducted by adding the sulfonium salt, for example, thedimethylmethylthiosulfonium fluoborate, to the ergoline of Formula II inan inert solvent such as dioxane or tetrahydrofuran. The reaction isterminated after 0.5-2 hours at room temperature.

Where the substituent R² signifies an acyl group, then the process isperformed by reacting the ergoline of Formula II with the acyl chloridein the presence of a Lewis acid, e.g., aluminum trichloride. However, ifthe acyl chloride is not in liquid form, then nitrobenzene orchlorobenzene can be utilized as the solvent. The reaction is preferablyconducted at temperatures below room temperature, such as -10° to -5°C., and is finished after 1-5 hours.

Any carbonyl groups that may be present in substituent R² can be reducedto hydroxy groups with a complex metal hydride. Such metal hydrides maybe sodium borohydride in a protonic or aprotic solvent, e.g.,tetrahydrofuran, acetonitrile, dioxane, dimethoxyethane, methanol,ethanol or isopropanol. Anhydrous calcium chloride may be added,preferably at the boiling temperature of the solvent employed or of thereaction mixture.

The oxidation of the methylthio group to the sulfoxide takes place withan aqueous solution of sodium periodate in acetonitrile. After severalhours, the reaction is terminated at 50° C.

The compounds of this invention according to Formula I wherein R² isC₁₋₃ -alkyl which can be substituted with OH or phenyl; C₂₋₃ -alkenyl;CONHR'; CSNHR'; COOR', wherein R' means H or C₁₋₃ -alkyl; or ##STR12##wherein R" means lower alkyl of up to 4 carbon atoms, can be preparedfrom compounds of Formula III ##STR13## wherein C₈ - - - C₉, C₉ - - -C₁₀, R⁶ and R⁸ having the meanings given above and

R¹ stands for

Si(R')₂ R (R'=methyl or phenyl and R=C₁₋₄ -alkyl), for C₁₋₇ -alkyl orC₇₋₉ -aralkyl or for C₂₋₅ -acyl or arylsulfonyl.

In the first stage of preparation, a 2-bromoergoline derivative ofFormula III is reacted with an alkyllithium or with phenyllithium at lowtemperatures in an inert solvent to form the corresponding 2-lithiumergoline derivative of Formula IV ##STR14## C₈ - - - C₉, C₉ - - - C₁₀,R¹, R⁶ and R⁸ have the meanings given above. Especially suitable as thealkyllithium is tert-butyllithium. The desired compounds may then beprepared from Formula IV by conventional methods.

The substituent R¹ occurring in the starting compounds of Formula III inthe 1-position has the function of a blocking group. The blocking groupR¹ can represent a silyl group of the formula Si(R'₂)R wherein R' is alower alkyl residue of up to four carbon atoms. However, R¹ can also bean alkyl group of up to seven carbon atoms, an aralkyl group of 7-9carbon atoms, an acyl residue of 2-5 carbon atoms, or an arylsulfonylresidue, such as the p-toluenesulfonyl residue.

Alkyl residues of up to seven carbon atoms are, besides the above-citedlower alkyl residues, for example, n-pentyl, n-hexyl, 1-methylpentyl and2,2-dimethylbutyl. Aralkyl groups are, for example, benzyl andphenethyl. Acyl groups of 2-5 carbon atoms are derived from aliphaticcarboxylic acids, such as acetic acid, propionic acid, butyric acid,caproic acid and trimethylacetic acid.

Low temperatures include temperatures below 0° C., especially those inthe range from -110° to -70° C. These temperatures are attained, forinstance, by the use of solid carbon dioxide or liquid nitrogen inmethanol, ether, or similar solvents as the coolants.

Suitable as solvents for the reaction are those showing inert behaviorunder the aforementioned reaction conditions, for example, aliphatic andaromatic hydrocarbons, such as hexane and toluene, or ethers, such astetrahydrofuran, dioxane and diethyl ether. The addition of astoichiometric quantity of tetramethylenediamine, based on thealkyllithium, is advantageous. The reaction is completed after a shortperiod of time, i.e., after about 2-10 minutes.

The 2-lithium ergoline derivative of formula IV prepared by the abovereaction is stable at low temperatures. The reaction solution need notbe given further work up and is used directly in the subsequent reactionstage. In this reaction stage, the 2-lithium ergoline derivative isreacted in an inert solvent with an electrophilic reagent, includingcarbon dioxide, ethylene oxide, methyl isocyanate, methylthioisocyanate, lower alkyl chlorosilane, lower alkyl and lower alkenylbromide or iodide and including alkyl disulfides, such as dimethyldisulfide or tetraisopropylthiuram disulfide, at low temperatures in therange from -110° to -50° C.

Where the reactant is a gas, then the latter is piped in or is made toreact with the 2-lithium ergoline derivative in the solid phase, assolid carbon dioxide, for example, and in a pressure vessel.

If the substituent in the 2-position represents a free carboxy function,then the latter can be esterified, if desired, by conventional methodssuch as reacting the ergoline with an aliphatic alcohol of the formulaROH wherein R is a C₁₋₄ -alkyl residue. For example, theergoline-2-carboxylic acid can be reacted with the alcohol in thepresence of an inorganic acid, such as hydrochloric or perchloric acid,at room temperature, to produce the ergolinyl ester.

Conventional methods are likewise employed for preparing compounds ofFormula I wherein

R² is

the grouping COR' or CSR' wherein R' is OH, OC₁₋₄ -alkyl, benzyl, NH₂ orNHR";

the grouping CH═CH--CO₂ R" or CH₂ --CH₂ --CO₂ R" wherein R" is C₁₋₄-alkyl;

the grouping C.tbd.C--R"' and HC═CH--R"' wherein R"' is hydrogen, C₁₋₄-alkyl, phenyl, CH₂ OH, CR"₂ OH, ##STR15## CO₂ R", CH₂ NR"₂, SiMe₂ R";or ##STR16## wherein R" means lower alkyl of up to 4 carbon atoms.

For this purpose, a 2-iodo- or 2-bromoergoline of Formula V ##STR17##wherein C₈ - - - C₉, C₉ - - - C₁₀, R⁶ and R⁸ have the meanings givenabove, is reacted with an electrophilic reagent, such as benzyl alcoholunder a carbon monoxide atmosphere, an acrylic ester (CH₂ ═CH--CO₂ R")or a monosubstituted acetylene (CH.tbd.CR"'), in the presence of apalladium catalyst and a secondary or tertiary amine, without a solventor in an aprotic water-miscible solvent, at temperatures of above roomtemperature in the range from 40° C. to the boiling temperature of thereaction mixture; and optionally, subsequently, the 2-benzyl gorup ishydrogenated with palladium with formation of the carboxy compound, oris reacted with ammonia to the 2-carboxylic acid amide group; or anexocyclic multiple bond is hydrogenated with Raney nickel or palladiumon a support to the CC-single bond or double bond; or a SiMe₂R"-blocking group is split off with a base or a tetrahydropyranylblocking group is split off with pyridinium p-toluenesulfonate,

Monosubstituted acetylene refers to ethynyl derivatives wherein anH-atom is substituted by C₁₋₃ -alkyl, phenyl, hydroxymethyl,tetrahydropyranyloxy, C₁₋₃ -alkoxycarbonyl, di-C₁₋₃ -alkylaminomethyl orC₁₋₃ -alkyl dimethylsilyl. Acrylic esters have 1-3 C-atoms in thealcohol portion.

The reaction with the acrylic ester or the acetylenic compound may beperformed in the absence of solvent, in the corresponding amine, or inan aprotic, water-miscible solvent in the presence of a secondary ortertiary amine.

Secondary and tertiary amines include, for example, dimethylamine,diethylamine, piperidine, triethylamine and tri-n-butylamine. Aprotic,water-miscible solvents include dimethylformamide, N-methylpyrrolidonetetrahydrofuran, acetonitrile and dioxane. The reaction is performed attemperature above room temperature in the range from 40° C. to theboiling temperature of the reaction mixture. The reaction isadditionally performed in the presence of a palladium catalyst.

Suitable palladium catalysts are palladium salts and palladium complexcompounds, e.g., palladium(II) acetate,trans-dichlorobis(tri-o-tolylphosphine) palladium(II),trans-dichlorobis(triphenylphosphine) palladium(II) and palladium(O)tetrakistriphenylphospine. The catalyst is used in an amount of 0.01-0.1mole, based on the 2-haloergoline that is used.

In some reactions, an addition of copper(I) iodide or oftri-o-tolylphosphine proved to be advantageous.

The reactions are performed in the absence of air and often underelevated pressure, e.g., in an inert gas atmosphere and in an autoclave.

Where the substituent R' means hydroxy, then the corresponding2-carboxylic acid benzyl ester is hydrogenated under normal pressure atroom temperature in a protonic solvent, such as an aliphatic alcohol,e.g., methanol, in the presence of finely divided palladium, such aspalladium black.

Where the substituent R' means an amino group, then the corresponding2-benzyl ester is reacted with the corresponding carboxylic acid amideand ammonia at elevated temperatures and in a protonic solvent such asan alcohol, preferably ethylene glycol.

Where the substituent in the 2-position contains an exocyclic C═C doublebond or C.tbd.C-triple bond, the unsaturated bond can be readilyentirely or partially reduced, e.g., with Raney nickel or palladium oncarbon to the corresponding hydrogenation product. The reduction isperformed in an aliphatic alcohol at room temperature under normalpressure.

Where the ethynyl substituent in the 2-position contains a blockinggroup, such as an SiMe₂ R"-group, then this group can be removed at roomtemperature with a weak base, such as sodium or potassium carbonate. Theblocking group can also be removed with acids or fluoride ions, e.g.,cesium fluoride or tetrabutylammonium fluoride. If the ethynyl group isblocked unilaterally as an acetone addition product, then the blockinggroup can be removed by boiling at 100° C. with a strong base, such aspotassium or sodium hydroxide.

Where the blocking group is the tetrahydropyranyl residue, the removalstep is conducted at 70°-100° C. in an acid solution such as pyridiniump-toluenesulfonate or dilute sulfuric acid in an alcohol.

The resultant compounds of Formula I are purified by recrystallizationand/or chromatography either as the free bases or, if desired, in theform of their acid addition salts. The salts may be obtained by reactionwith a physiologically compatible acid such as tartaric acid or maleicacid. For the formation of salts, the compounds of Formula I aredissolved in a small amount of methanol or methylene chloride andcombined at room temperature with a concentrated solution of the desiredacid in methanol.

The starting compounds necessary for performing the process of thisinvention are either known or can be prepared according to methods knownto a person skilled in the art. Some sample preparations follow.

Preparation of the Starting Materials

A solution is prepared from 1 mmol of terguride in 20 ml of anhydrousdioxane, combined with about 1.5 ml of N-iodosuccinimide at roomtemperature and stirred for 30 minutes. The reaction mixture is thenpoured into a saturated bicarbonate solution, extracted with methylenechloride and the organic phase is dried with magnesium sulfate. Afterevaporation of the solvent, the residue is chromatographed on silicagel, thus obtaining in a 76% yield1,1-diethyl-3-(2-iodo-6-methyl-8α-ergolinyl)urea.

[α]_(D) =+37.3° c=0.2 in pyridine.

Analogously, lisuride and N-bromosuccinimide yield1,1-diethyl-3-(2-bromo-6-methyl-9,10-didehydro-8α-ergolinyl)urea (23%).

[α]_(D) =+247° c=0.2 in pyridine.

In a likewise analogous way, lisuride and N-iodosuccinimide yield1,1-diethyl-3-(2-iodo-6-methyl-9,10-didehydro-8α-ergolinyl)urea (20%).

Under ice cooling, a solution of lithium diisopropylamide is preparedfrom 27 ml of 15% strength n-butyllithium in hexane (67 mmol), 9.1 ml ofanhydrous diisopropylamine and 40 ml of anhydrous tetrahydrofuran. Thissolution is cooled to -20° C. and a solution of 12.7 g ofbromoagroclavine (30 mmol) in 115 ml of anhydrous tetrahydrofuran isadded dropwise thereto; the mixture is agitated at this temperature for15 minutes and then 7.3 ml of tert-butyldimethylsilyl chloride (48 mmol)in 15 ml of anhydrous tetrahydrofuran is added thereto. This mixture isallowed to heat up to room temperature and agitated for 2 days. Themixture is distributed between ethyl acetate and bicarbonate solution;the organic phase is dried over sodium sulfate and evaporated. Theresidue is chromatographed on silica gel with methylene chloride, thenwith methylene chloride/methanol, yielding2-bromo-1-(tert-butyldimethylsilyl)-8,9-didehydro-6,8-dimethylergolinein an 83% yield.

[α]_(D) =-161° (0.5% in chloroform).

The following compounds are produced analogously:

3-[2-bromo-1-(tert-butyldimethylsilyl)-9,10-didehydro-6-methyl-8α-ergolinyl]-1,1-diethylurea,yield: 72% of theory;

3-[2-bromo-1-(tert-butyldimethylsilyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea,yield: 63% (from diisopropyl ether), [α]_(D) =+6° (0.5% fromchloroform);

3-[2-bromo-1-(tert-butyldiphenylsilyl)-9,10-didehyro-6-methyl-8α-ergolinyl]-1,1-diethylurea;yield: 29%, [α]_(D) =+183° (0.5% in chloroform);

3-[2-bromo-1-(tert-butyldiphenylsilyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea,yield: 19%, [α]_(D) =-0.6° (0.5% in chloroform);

3-[2-bromo-1-(tert-butyldimethylsilyl)-9,10-didehydro-6-methyl-8α-ergolinyl]-1,1-diethylthiourea;

3-[2-bromo-1-(tert-butyldimethylsilyl)-6-methyl-8α-ergolinyl]-1,1-diethylthiourea;

3-[2-bromo-1-(tert-butyldimethylsilyl)-6-methyl-8β-ergolinyl]-1,1-diethylurea,yield: 65%, [α]_(D) =-80° (0.5% in chloroform);

3-[2-bromo-1-(tert-butyldimethylsilyl)-n-propyl-8α-ergolinyl]-1,1-diethylurea,yield: 77%, [α]_(D) =-5° (0.5% in chloroform).

2.7 g of bromoagroclavine (8.5 mmol) is dissolved in 400 ml of methylenechloride; 0.4 g of tetrabutylammonium hydrogen sulfate, 2.1 g ofpulverized potassium hydroxide and 2.1 ml of trimethylacetic acidchloride are added, and the mixture is stirred for 30 minutes at roomtemperature. Then ice is added, the mixture is again stirred for 30minutes at room temperature and extracted with bicarbonate solution andadditional methylene chloride. After evaporation an chromatography onsilica gel with methylene chloride and methanol, 2.6 g of2-bromo-8,9-didehydro-6,8-dimethyl-1-(trimethylacetyl)ergoline isobtained (76% of theory).

[α]_(D) =-104° (0.5% in chloroform).

The following acyl compounds are prepared in an analogous way:

2-bromo-8,9-didehydro-6,8-dimethyl-1-(tert-butoxycarbonyl)ergoline,yield: 69%; [α]_(D) =-121° (0.5% in chloroform);

2-bromo-8,9-didehydro-6,8-dimethyl-1-(4-methoxy-2,3,6-trimethylphenylsulfonyl)ergoline;yield: 74% (after chromatography) and 41% (after recrystallization frommethanol), respectively, [α]_(D) =-142° (0.5% in chloroform);

2-bromo-8,9-didehydro-6,8-dimethyl-1-(2,4,6-trimethoxyphenylsulfonyl)ergoline,yield: 81% (from methanol).

The invention furthermore relates to a novel process for producing2-(trialkylsilyl)ergoline derivatives of Formula I, a2-bromo-1-(trialkylsilyl)ergoline of general Formula VI ##STR18##wherein C₈ - - - C₉, C₉ - - - C₁₀, R, R⁶ and R⁸ have the above meanings,is reacted with an alkyllithium at temperatures of below 0° C.,optionally in the presence of a tertiary amine, when R² in Formula I isthe grouping ##STR19## wherein R"=C₁₋₄ -alkyl and is subsequently, ifdesired, converted into the acid addition salt with a physiologicallycompatible acid.

2-(trialkylsilyl)ergoline derivatives can be prepared per se byelectrophilic substitution of compounds metallized in the 2-position.This novel procedure has not been disclosed heretofore in connectionwith ergoline derivatives; however, the process shows onlyunsatisfactory yields. It is an additional object of the presentinvention to provide a process for preparation of2-(trialkylsilyl)ergoline derivatives which affords better yields.

It has now been found surprisingly that the preparation of2-(trialkylsilyl)ergoline derivatives is highly successful if2-bromo-1-trialkylsilyl)ergoline derivatives are reacted in a cyclicether with an alkyllithium, and the product is rearranged to thecorresponding 2-(trialkylsilyl)ergoline compound. The process of thisinvention is conducted by reacting the 2-bromo-1-(trialkylsilyl)ergolineat low temperatures, e.g., below 0° C., especially -70° to -20° C. Thesetemperatures can be obtained by using coolants such as solid carbondioxide in methanol and/or methylene chloride. Cyclic ethers are used asa solvent, preferably tetrahydrofuran and dioxane. The solvent is usedin great excess, preferably in about 10-500 fold quantity. Analkyllithium is added to the reaction mixture in an amount of 1-5equivalents and the product is rearranged after a prolonged reactionperiod into the corresponding 2-silylergoline derivative.Tertbutyllithium is especially suitable as the alkyllithium. Dependingon the chemical structure of the ergoline employed as the startingmaterial, a tertiary amine, such as tetramethylethylenediamine, can beadded to the reaction mixture. The isomerization is terminated after afew hours, i.e., after 2-8 hours.

The course of the process according to this invention is surprisinginsofar as the rearrangement reaction does not occur in other solventscustomary in silylation reactions, such as toluene or benzene.

The following example demonstrates this fact.

800 mg of2-bromo-1-(tert-butyldimethylsilyl)-8,9-didehydro-6,8-dimethylergolinewas dissolved in 50 ml of anhydrous toluene; the solvent was distilledoff under vacuum and the mixture taken up in 75 ml of anhydrous, freshlydistilled toluene under an argon atmosphere. To this solution was added1 ml of anhydrous tetramethylethylenediamine and the mixture was cooledto -90° C. Then the mixture was combined with 6.0 ml of 1.4-molartert-butyllithium solution in hexane (8.4 mmol) and agitated for 5hours. Water was then added, the mixture was extracted with methylenechloride, the organic phase was dried with sodium sulfate andevaporated. In a quantitative yield, 8,9-didehydro-6,8-dimethylergolinewas isolated. The desired8,9-didehydro-6,8-dimethyl-2-trimethylsilylergoline could not bedetected by NMR.

The starting compounds needed for conducting the process of thisinvention are either known or can be prepared according to methods knownto those skilled in the art. For example "Die Mutterkornalkaloide" by A.Hoffmann, Enke-Verglag Stuttgart, 1964, and "Lisuride and OtherAgonists" by D. B. Calne, R. Horowski, R. G. McDonald and W. Wuttke,Raven Press, NY, 1983.

Under ice cooling, a solution of lithium diisopropylamide is preparedfrom 27 ml of 15% n-butyllithium in hexane (67 mmol), 9.1 ml ofanhydrous diisopropylamine and 40 ml of anhydrous tetrahydrofuran. Thissolution is cooled to -20° C. and a solution of 12.7 g ofbromoagroclavine (30 mmol) in 115 ml of anhydrous tetrahydrofuran isadded dropwise thereto; the mixture is agitated for 15 minutes at thistemperature, and then 7.3 ml of tert-butyldimethylsilyl chloride (48mmol) in 15 ml of anhydrous tetrahydrofuran is added thereto. Thismixture is allowed to heat up to room temperature and agitated for 2days. The mixture is distributed between ethyl acetate and bicarbonatesolution, the organic phase is dried over sodium sulfate and evaporated.The residue is chromatographed on silica gel with methylene chloride,then with methylene chloride/methanol. Yield:2-bromo-1-(tert-butyldimethylsilyl)-8,9-didehydro-6,8-dimethylergoline,the starting material of the previous example, in an 83% yield,

[α]_(D) =-161° (0.5% in chloroform).

The following compounds are produced analogously:

3-[2-bromo-1-(tert-butyldimethylsilyl)-9,10-didehydro-6-methyl-8α-ergolinyl]-1,1-diethylurea,yield: 72% of theory;

3-[2-bromo-1-(tert-butyldimethylsilyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea,yield: 63% (frm diisopropyl ether), [α]_(D) =+6° (0.5% from chloroform);

3-[2-bromo-1-(tert-butyldimethylsilyl)-9,10-didehydro-6-methyl-8α-ergolinyl]-1,1-diethylthiourea;

3-[2-bromo-1-(tert-butydimethylsilyl)-6-methyl-8α-ergolinyl]-1,1-diethylthiourea;

3-[2-bromo-1-(tert-butyldimethylsilyl)-6-methyl-8β-ergolinyl]-1,1-diethylurea,yield: 65%, [α]_(D) =-80° (0.5% in chloroform); and

3-[2-bromo-1-(tert-butyldimethylsilyl)-n-propyl-8α-ergolinyl]-1,1-diethylurea,yield: 77%, [α]_(D) =-5° (0.5% in chloroform).

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever. In the followingexamples, all temperatures are set forth uncorrected in degrees Celsius;unless otherwise indicated, all parts and percentages are by weight.

EXAMPLE 1

680 mg of terguride (2 mmol) is dissolved in 120 ml of acetonitrile and5.5 ml of triethylamine and, under ice cooling, a solution of 3.5 ml ofchlorosulfonyl isocyanate in 40 ml of acetonitrile is added dropwisethereto under an argon atmosphere. The ice bath is removed and themixture allowed to stand for two days at room temperature. To facilitateisolation of the polar by-products, the mixture is combined with 20 mlof diethylamine and stirred for three hours at room temperature. Thenthe mixture is diluted with methylene chloride, extracted with 1N sodiumhydroxide solution, and the water phase is once more extracted. Thecombined organic phases are dried with sodium sulfate and evaporated.The residue is chromatographed on silica gel with a mixture of methylenechloride and methanol, thus isolating 229 mg (31% of theory) of crude3-(2-cyano-6-methyl-8α-ergolinyl)-1,1-diethylurea. Ater crystallizingfrom ethyl acetate, 92 mg is obtained as the pure compound.

[α]_(D) =+20° (0.1% in chloroform)

The polar by-products are acylation products in the 1- and/or2-position.

EXAMPLE 2

507 mg of lisuride (1.5 mmol) is dissolved in 30 ml of tetrahydrofuranand, at room temperature under nitrogen, 588 mg ofdimethylmethylthiosulfonium fluoborate (3 mmol) is added. After 30minutes of agitation at room temperature, the mixture is distributedbetween methylene chloride and bicarbonate solution, the organic phasesare combined, dried with sodium sulfate and evaporated. The crudeproduct is chromatographed on silica gel with methylene chloride andmethanol; the yield is 506 mg (82% of theory) of3-(9,10-didehydro-6-methyl-2-methylthio-8α-ergolinyl)-1,1-diethylurea,from which the tartrate is produced.

Yield: 208 mg (55% of theory); [α]_(D) =+226° (0.5% in pyridine).

The following compounds are prepared analogously:

From terguride

1,1-diethyl-3-(6-methyl-2-methylthio-8α-ergolinyl)urea, yield: 58%(after chromatography), tartrate (79% yield): [α]_(D) =+23° (0.5% inpyridine).

From 8,9-didehydro-6,8-dimethylergoline8,9-didehydro-6,8-dimethyl-2-methylthioergoline, yield: 95% (afterchromatography), tartrate (40% yield): [α]_(D) =-172° (0.1% inpyridine).

From 3-(6-methyl-8α-ergolinyl)-1,1-diethylthiourea1,1-diethyl-3-(6-methyl-2-methylthio-8α-ergolinyl)thiourea, yield: 26%,[α]_(D) =+54° (0.5% in chloroform).

From 1,1-diethyl-3-(6-methyl-8β-ergolinyl)urea1,1-diethyl-3-(6-methyl-2-methylthio-8β-ergolinyl)urea, [α]_(D) =-100°(0.1% in chloroform), yield: 47%.

From 1,1-diethyl-3-(6-n-propyl-8α-ergolinyl)urea1,1-diethyl-3-(2-methylthio-6-n-propyl-8α-ergolinyl)urea, yield: 62%,[α]_(D) =+7° (0.5% in chloroform).

EXAMPLE 3

Under ice cooling, 3 ml (42 mmol) of acetyl chloride is combined with0.467 g (3.5 mmol) of anhydrous aluminum chloride and, at -10° C., with0.477 g (1.4 mmol) of 3-(6-methyl-8α-ergolinyl)-1,1-diethylurea. After2.5 hours of agitation at -5° to 0° C., 30 ml of hexane is added and themixture decanted from the oily sediment, which latter is taken up inmethylene chloride/water. The organic phase is washed with 10% sodiumbicarbonate solution and with saturated sodium chloride solution, driedover magnesium sulfate and concentrated. Column chromatography over 150g of silica gel with methylene chloride/ethanol 10:1 andrecrystallization from ethanol/hexane yield 134 mg (25%) of3-(2-acetyl-6-methyl-8α-ergolinyl)-1,1-diethylurea, mp 114°-116° C.

[α]_(D) =+51° (0.2% in pyridine).

The following compounds are produced in an analogous way:

2-acetyl-8,9-didehydro-6,8-dimethylergoline (mp 168°-169° C.),ethanol/hexane, from 8,9-didehydro-6,8-dimethylergoline;

3-(2-propionyl-6-methyl-8α-ergolinyl)-1,1-diethylurea from terguride;and

3-(2-acetyl-9,10-didehydro-6-methyl-8α-ergolinyl)-1,1-diethylurea fromlisuride.

EXAMPLE 4

57 mg (0.149 mmol) of 3-(2-acetyl-6-methyl-8α-ergolinyl)-1,1-diethylureain 4 ml of absolute tetrahydrofuran is heated under reflux for 2 hourswith 38 mg (1 mmol) of sodium borohydride and 18 mg (0.162 mmol) ofanhydrous calcium chloride. After cooling to room temperature andaddition of water, the mixture is stirred for 10 minutes, thetetrahydrofuran is removed by distillation, and the mixture is combinedwith methylene chloride. Washing of the organic phase with saturatedsodium chloride solution and drying over magnesium sulfate yield, afterconcentration and column chromatographing of the crude product over 75 gof silica gel with methylene chloride/ethanol=5:1, 26 mg (46.6%) of3-[2-(1-hydroxyethyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea as an oilthat is crystallized throughout; mp starting with 175° C.

The following compounds are prepared analogously:

From 3-(2-acetyl-9,10-didehydro-6-methyl-8α-ergolinyl)-1,1-diethylurea;3-[2-(1-hydroxyethyl)-9,10-didehydro-6-methyl-8α-ergolinyl]-1,1-diethylurea,

from 3-(2-propionyl-6-methyl-8α-ergolinyl)-1,1-diethylurea,3-[2-(1-hydroxypropyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea, and

from 2-acetyl-8,9-didehydro-6,8-dimethylergoline,2-(1-hydroxyethyl)-8,9-didehydro-6,8-dimethylergoline.

EXAMPLE 5

210 mg of 1,1-diethyl-3-(6-methyl-2-methylthio-8α-ergolinyl)urea isdissolved in 20 ml of acetonitrile, and 0.5 g of sodium metaperiodate in5 ml of water is added thereto in incremental portions. The mixture isstirred at 50° C. for 16 hours, the residue is distributed betweenmethylene chloride and water, the organic phase is dried with sodiumsulfate and evaporated. The residue is chromatographed on silica gel.Yield: 109 mg of1,1-diethyl-3-(6-methyl-2-methylsulfinyl-8α-ergolinyl)urea.

[α]_(D) =+13° (0.5% in chloroform).

EXAMPLE 6

800 mg of3-[2-bromo-1-(tert-butyldimethylsilyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea(1.5 mmol) is dissolved in 50 ml of anhydrous toluene, the solvent isdistilled off under vacuum, and the mixture is taken up with 75 ml ofanhydrous, freshly distilled toluene under an argon atmosphere. To thissolution is added 1 ml of anhydrous tetramethylethylenediamine and themixture is cooled to -90° C. Then the mixture is combined with 6.0 ml of1.4-molar tert-butyllithium solution in hexane (8.4 mmol) and stirredfor 2 minutes, thus obtaining a soltion of3-[1-(tert-butyldimethylsilyl)-2-lithium-6-methyl-8α-ergolinyl]-1,1-diethylurea,which is used in the subsequent stage.

The thus-prepared solution of the 2-lithium ergoline is combined with asolution of 0.6 ml of methyl isocyanate (9 mmol) in 4 ml of toluene andstirred for 30 minutes at -70° C. Then water is added, the mixture isextracted with methylene chloride, the organic phase is dried withsodium sulfate and evaporated. The residue is chromatographed on silicagel with methylene chloride and methanol, thus isolating 142 mg of8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid methylamide(24% of theory). Crystallization from methylene chloride and diisopropylether yields 87 mg (15% of theory).

[α]_(D) =+50° (0.2% in pyridine).

The following compounds are produced analogously:

9,10-didehydro-8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acidmethylamide, yield: 16%, [α]_(D) =+284° (0.1% in pyridine);

8,9-didehydro-6,8-dimethylergoline-2-carboxylic acid methylamide, yield:51%, [α]_(D) =-162° (0.5% in chloroform).

By replacing methyl isocyanate by methyl isothiocyanate, the followingcompounds are obtained:

8α-(3,3-diethylureido)-6-methylergoline-2-thiocarboxylic acidmethylamide, yield: 52%, [α]_(D) =+22° (0.2% in pyridine);

9,10-didehydro-8α-(3,3-diethylureido)-6-methylergoline-2-thiocarboxylicacid methylamide, yield: 22%, [α]_(D) =+319° (0.1% in pyridine);

8,9-didehydro-6,8-dimethylergoline-2-thiocarboxylic acid methylamide,yield: 58%, [α]_(D) =-328° (0.2% in pyridine).

By using trimethylsilyl isocyanate in place of methyl isocyanate:

8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid amide, yield:47%; [α]_(D) =+42° (0.2% in pyridine).

With the trimethylsilyl ester of trifluoromethylsulfonic acid in placeof methyl isocyanate:

8,9-didehydro-6,8-dimethyl-2-trimethylsilylergoline, yield: 15% [α]_(D)=-177° (0.5% in chloroform), and

1,1-diethyl-3-(6-methyl-2-trimethylsilyl-8α-ergolinyl)urea, yield: 35%;[α]_(D) =+30° (0.5% in chloroform).

With methyl iodide in place of methylisocyanate:

3-(2,6-dimethyl-8α-ergolinyl)-1,1-diethylurea.

With carbon dioxide in place of methyl isocyanate:

A solution of 2-lithium ergoline prepared as described above is quicklypoured on maximally dry, solid CO₂. The mixture is sealed into apressure vessel where it is heated up to room temperature. Next morning,the vessel is gently opened and the content worked up as usual. Thereaction product is purified by chromatography.

8,9-didehydro-6,8-dimethylergoline-2-carboxylic acid, yield: 60%,[α]_(D) =-152° (0.1% in pyridine);

9,10-didehydro-8α-(3,3-diethylureido)-6-methylergoline-2-carboxylicacid, yield: 42%, [α]_(D) =+187° (0.2% in methanol);

8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid, yield: 48%,[α]_(D) =+27° (0.2% in methanol).

By replacement of methyl isocyanate with dimethyl disulfide:

1,1-diethyl-3-(6-methyl-2-methylthio-8α-ergolinyl)urea, yield: 67%; fromthis, the tartrate in an 80% yield. [α]_(D) =+23° (0.5% in pyridine).

With tetraisopropylthiuram disulfide:

8,9-didehydro-6,8-dimethylergolin-2-yl-(N,N-diisopropyl)dithiocarbamate,yield: 65%; [α]_(D) =-144° (0.5% in chloroform);bis-[8α-(3,3-diethylureido)-6-methyl-2-ergolinyl]disulfide.

EXAMPLE 7

Esterification of the free ergoline-2-carboxylic acids obtained inExample 6 with methanol yields the respective methyl esters by allowingthe mixture to stand at room temperature in methanolic hydrochloricacid:

8,9-didehydro-6,8-dimethylergoline-2-carboxylic acid methyl ester,yield: 42%, [α]_(D) =-266° (0.5% in chloroform);

9,10-didehydro-8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acidmethyl ester, yield: 46%, tartrate, yield: 57%, [α]_(D) =+217° (0.1% inpyridine);

8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid methyl ester,yield: 50%, tartrate, yield: 60%, [α]_(D) =+33° (0.1% in pyridine).

EXAMPLE 8

Under an argon atmosphere, 730 mg of2-bromo-8,9-didehydro-6,8-dimethyl-1-(trimethylacetyl)ergoline (1.5mmol) is dissolved in 60 ml of anhydrous toluene, 1 ml of anhydroustetramethylethylenediamine is added to this solution, and the latter iscooled to -90° C. Then the mixture is combined with 1.4 ml oftert-butyllithium solution in hexane (8.4 mmol) and stirred for 2minutes. The resultant solution of8,9-didehydro-6,8-dimethyl-2-lithium-1-trimethylacetylergoline isquickly poured on dry, solid carbon dioxide and sealed into a pressurevessel. Next morning, the vessel is gently opened and the reactionmixture worked up as usual, thus obtaining8,9-didehydro-6,8-dimethylergoline-2-carboxylic acid in a 51% yield.[α]_(D) =-151° (0.1% in pyridine).

EXAMPLE 9

As described in Example 6,3-[2-bromo-1-(tert-butyldimethylsilyl)-6-methyl-8β-ergolinyl]-1,1-diethylureaand tert-butyllithium are employed to produce the corresponding2-lithium compound. The latter is reacted with dimethyl disulfide,instead of with methyl isocyanate, thus producing1,1-diethyl-3-(6-methyl-2-methylthio-8β-ergolinyl)urea, yield: 54%.[α]_(D) =-100° (0.1% in methanol).

EXAMPLE 10

Analogously to Example 6,3-[2-bromo-1-(tertbutyldimethylsilyl)-6-n-propyl-8α-ergolinyl]-1,1-diethylurea yields, with tert-butyllithium, the corresponding lithium compound,and from the latter, using dimethyl disulfide,1,1-diethyl-3-(2-methylthio-6-n-propyl-8α-ergolinyl)urea is prepared.

Yield: 51%; [α]_(D) =+6° (0.5% in chloroform).

EXAMPLE 11

300 mg (0.644 mmol) of 3-(2-iodo-6-methyl-8α-ergolinyl)-1,1-diethylureais heated, after adding 0.169 ml (0.709 mmol) of tri-m-butylamine, in 4ml of benzyl alcohol, combined under a carbon monoxide atmosphere with 7mg (0.031 mmol) of palladium(II) acetate, and kept at 100°-110° C. for2.5 hours under vigorous agitation. After cooling to room temperature,the reaction solution is diluted with ethyl acetate and extracted withsaturated sodium bicarbonate solution and saturated sodium chloridesolution. After drying over magnesium sulfate, the ethyl acetate isremoved by distillation under reduced pressure and then the benzylalcohol is distilled off under a high vacuum. By column chromatographyon 150 g of silica gel in a system of dichloromethane/ethanol=10:1 andrecrystallization from ethanol/hexane, 166 mg of8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid benzyl esteris produced from the crude product (54.5%), mp 226°-229° C.

[α]_(D) =+43.2° (c=0.25% in pyridine).

EXAMPLE 12

104 mg (0.22 mmol) of8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid benzyl esteris dissolved in 20 ml of methanol and, after adding 50 mg of palladiumblack, hydrogenated for 30 minutes under normal pressure at roomtemperature. After the catalyst has been filtered off and the mixtureconcentrated, 8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acidis obtained in a 100% yield, mp: decomposition starting with 230° C.

EXAMPLE 13

150 mg (0.31 mmol) of8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid benzyl esteris heated in 3 ml of a saturated solution of ammonia in ethylene glycolfor 3 hours to 100° C. After dilution with water, the mixture isextracted with ethyl acetate and the organic phase washed with saturatedsodium chloride solution, dried over magnesium sulfate, filtered, andconcentrated. The residue is chromatographed over silica gel withmethylene chloride/ethanol=8:1. After trituration inethanol/hexane/ether, 90 mg of8α-(3,3-diethylureido)-6-methylergoline)-2-carboxylic acid amide isobtained, mp 171°-173° C.

[α]_(D) =+42.5° (c=0.2% in pyridine).

EXAMPLE 14

A solution is prepared from 261 mg (0.56 mmol) of3-(2-iodo-6-methyl-8α-ergolinyl)-1,1-diethylurea, 7.0 mg (0.023 mmol) oftri-o-tolyl phosphine, 4.7 mg (0.006 mmol) oftrans-dichlorobis(tri-o-tolyl phsophine) palladium(II) and 0.075 ml(0.69 mmol) of ethyl acrylate in 1.5 ml of dimethylformamide and 0.7 mlof triethylamine; after purging with argon, the solution is heated in anautoclave for 4 hours to 100° C. After concentrating the reactionsolution under reduced pressure, it is taken up in ethyl acetate andwashed with saturated sodium chloride solution. The crude productobtained after drying of the ethyl acetate phase over magnesium sulfateand concentration of the solution is chromatographed over 150 g ofsilica gel with dichloromethane/ethanol 10:1 as the solvent, thusobtaining3-(2-ethoxycarbonylvinyl-6-methyl-8α-ergolinyl)-1,1-diethylurea.

Yield: 115 mg (47%), mp: 223°-225° C. (ethanol/hexane), [α]_(D) =+115°(c=0.2% in pyridine).

EXAMPLE 15

A solution is prepared from 178 mg (0.406 mmol) of3-[(2-ethoxycarbonylvinyl)-6-methyl-8α-ergolinyl)]-1,1-diethylurea in 20ml of ethanol and, after adding 0.1 g of Raney nickel, hydrogenated forone hour at room temperature under normal pressure. After the catalysthas been removed by filtration, 86 mg of3-[2-(2-ethoxycarbonylethyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea isobtained (48%), mp 160°-161° C., by recrystallizing from ethylacetate/hexane.

[α]_(D) =+22° (c=0.2% in pyridine).

EXAMPLE 16

933 mg (2.0 mmol) of 3-(2-iodo-6-methyl-8α-ergolinyl)-1,1-diethylurea isdissolved in a mixture of 5 ml of dimethylformamide and 10 ml oftriethylamine and, after addition of 0.610 ml (4.4 mmol) ofethynyltrimethylsilane, 19 mg (0.1 mmol) of copper(I) iodide, and 47.2mg (0.06 mmol) of trans-dichlorobis(tri-o-tolyl phosphine)palladium(II), heated for 3 hours under argon to 60° C. Afterconcentration under reduced pressure and taking up of the residue inethyl acetate/water, the organic phase is washed with saturated sodiumchloride solution, dried over magnesium sulfate, and evaporated. Columnchromatography over 150 g of silica gel with methylene chloride/ethanol10:1 as the eluent yields 486 mg of3-(2-ethynyltrimethylsilyl-6-methyl-8α-ergolinyl)-1,1-diethylurea(55.7%) as an oil.

The following compounds are produced analogously:

3-[6-methyl-2-[3-(tetrahydropyran-2-yloxy)propynyl]-8α-ergolinyl]-1,1-diethylurea,mp 188° C., [α]_(D) =+64° (c=0.2% in pyridine);

3-(2-propynyl-6-methyl-8α-ergolinyl)-1,1-diethylurea;

3-[2-(1-dimethylaminopropyn-3-yl)-6-methyl-8α-ergolinyl]-1,1-diethylurea;

1,1-diethyl-3-[2-(2-methoxy-1-propynyl)-6-methyl-8α-ergolinyl]urea, mp211°-214° C., [α]_(D) =+68.0° (c=0.2% in pyridine);

1,1-diethyl-3-[2-(3-hydroxy-3-methyl-1-butynyl)-6-methyl-8α-ergolinyl]urea,mp starting with 132°-140° C., [α]_(D) =+67.8° (c=0.2% in pyridine);

1,1-diethyl-3-(2-phenylethynyl-6-methyl-8α-ergolinyl)urea, mp 240°-242°C., [α]_(D) =+107.5° (c=0.2% in pyridine).

2-[2-(1-carbethoxyethyn-2-yl)-6-methyl-8α-ergolinyl]-1,1-diethylurea;

3-(2-trimethylsilylethynyl-6-methyl-8β-ergolinyl)-1,1-diethylurea;

3-(2-trimethylsilylethynyl-6-methyl-8α-ergolinyl)-1,1-diethylthiourea

3-(2-trimethylsilylethynyl-1,6-dimethyl-8α-ergolinyl)-1,1-diethylurea;

8,9-didehydro-6,8-dimethyl-2-phenylethynylergoline, mp starting with118° C. (decomposition); and

3-(2-trimethylsilylethynyl-6-n-propyl-8α-ergolinyl)-1,1-diethylurea.

EXAMPLE 17

Starting with 3-(2-bromo-6-methyl-8α-ergolinyl)-1,1-diethylurea,3-(tetrahydropyran-2-yloxy)-1-propyne yields3-[9,10-didehydro-6-methyl-2-[3-(tetrahydropyran-2-yloxy)-1-propynyl]-8.alpha.-ergolinyl]-1,1-diethylurea(25%) and 3-hydroxy-3-methyl-1-butyne yields3-[9,10-didehydro-2-(3-hydroxy-3-methyl-1-butynyl)-6-methyl-8.alpha.-ergolinyl]-1,1-diethylurea(31%).

EXAMPLE 18

262 mg (0.6 mmol) of3-(2-ethynyltrimethylsilyl-6-methyl-8α-ergolinyl)-1,1-diethylurea isdissolved in a mixture of 9 ml of ethanol and 1 ml of water and, afterthe addition of 104 mg (0.75 mmol) of anhydrous potassium carbonate,stirred for 16 hours at room temperature. The solvent is removed bydistillation, the mixture is taken up in ethyl acetate and extractedwith saturated sodium chloride solution. After drying the ethyl acetatesolution over magnesium sulfate, removing the solvent by distillation,and column chromatography of the crude product on 150 g of silica gelwith toluene/ethanol/water in a ratio of 80:20:1 as the eluent, 81 mg of3-(2-ethynyl-6-methyl-8α-ergolinyl)-1,1-diethylurea is obtained (37%) byrecrystallization from ethanol/hexane, mp 192° C.

[α]_(D) =60.6° (c=0.175% in pyridine).

The following compounds are prepared analogously:

3-(2-ethynyl-6-methyl-8α-ergolinyl)-1,1-diethylthiourea;

3-(2-ethynyl-1,6-dimethyl-8α-ergolinyl)-1,1-diethylurea; and

3-(2-ethynyl-6-n-propyl-8α-ergolinyl)-1,1-diethylurea, mp 126° C.

[α]_(D) =+65.9° (c=0.13% in pyridine).

EXAMPLE 19

Under nitrogen, 122 mg (0.29 mmol) of3-[9,10-didehydro-2-(3-hydroxy-3-methyl-1-butynyl)-6-methyl-8α-ergolinyl]-1,1-diethylureais heated for 2 hours under reflux in 15 ml of absolute toluene afteradding 64 mg (1.6 mmol) of pulverized sodium hydroxide. The solvent isthen removed by distillation and the residue extracted in ethyl acetatewith water and saturated sodium chloride solution. The crude productobtained from the ethyl acetate solution after drying with magnesiumsulfate and concentration is purified by column chromatography on 80 gof silica gel with ethyl acetate/ethanol 2:1 as the eluent.Reprecipitation from ethyl acetate/ether/hexane produces3-(9,10-didehydro-2-ethynyl-8α-ergolinyl)-1,1-diethylurea in a 25%yield.

[α]_(D) =+34° (c=0.2% in pyridine).

EXAMPLE 20

213 mg (0.45 mmol) of3-[6-methyl-2-[3-(tetrahydropyran-2-yloxy)propynyl]-8α-ergolinyl]-1,1-diethylureais heated under reflux in 10 ml of ethanol with 2 ml of water and 176 mg(0.7 mmol) of pyridinium p-toluenesulfonate under argon for one hour.After evaporation and distribution in ethyl acetate and saturatedbicarbonate solution, the organic phase is washed with saturated sodiumchloride solution, dried over magnesium sulfate, filtered andconcentrated. The residue is chromatographed over silica gel first withethyl acetate/acetone=1:1 and later with methylenechloride/acetone=12:1. Recrystallization from ethyl acetate/hexaneyields 90 mg (51%) of3-[2-(1-hydroxypropyn-3-yl)-6-methyl-8α-ergolinyl]-1,1-diethylurea, mp151°-154° C.

[α]_(D) =+71.2° (c=0.21% in pyridine).

The following compounds are prepared analogously:

3-[2-(1-hydroxypropyn-3-yl)-9,10-didehydro-6-methyl-8α-ergolinyl]-1,1-diethylurea,[α]_(D) =+404° (c=0.2 in pyridine), mp >129° C.

EXAMPLE 21

At room temperature and under normal pressure, 140 mg (0.084 mmol) of3-(2-ethynyl-6-methyl-8α-ergolinyl)-1,1-diethylurea is hydrogenated in20 ml of ethanol after addition of 0.1 g of Raney nickel within 45minutes. After the catalyst has been removed by filtration and thesolution has been concentrated, the product is recrystallized fromehtanol/hexane, yielding 119 mg of3-(2-ethyl-6-methyl-8α-ergolinyl)-1,1-diethylurea (84%), mp 165°-168°C., [α]_(D) =+25° (c=0.22 in pyridine).

The following compound is produced analogously:

1,1-diethyl-3-(6-methyl-2-phenethyl-8α-ergolinyl)urea, mp 175°-177° C.;[α]_(D) =+26° (c=0.1% in pyridine).

EXAMPLE 22

200 mg of 3-(2-ethynyl-6-methyl-8α-ergolinyl)-1,1-diethylurea ishydrogenated at room temperature and under normal pressure in 35 ml ofethanol with 200 mg of palladium/calcium carbonate (2%) and 200 mg ofquinoline. After the mixture has been filtered off from the catalyst, itis evaporated. The residue is chromatographed over silica gel withmethylene chloride/ethanol 6:1, thus obtaining 30 mg of3-(6-methyl-2-vinyl-8α-ergolinyl)-1,1-diethylurea afterrecrystallization from ethanol/hexane, mp 145°-150° C.;

[α]_(D) =+63.5° (c=0.22% in pyridine).

EXAMPLE 23

800 mg of3-[2-bromo-1-(tert-butyldimethylsilyl)-6-methyl-8α-ergolinyl]1,1-diethylurea(1.5 mmol) is dissolved in 75 ml of anhydrous, freshly distilledtetrahydrofuran under an argon atmosphere. To this solution is added 1ml of anhydrous tetramethylethylenediamine, and the mixture is cooled to-80° C. (bath temperature). Then the mixture is combined with 6.0 ml of1.4-molar tert-butyllithium solution in hexane (8.4 mmol), thusproducing a solution of3-[(1-tert-butyldimethylsilyl)-2-lithium-6-methyl-8α-ergolinyl)]-1,1-diethylureawhich is stirred at -70° C. for 5 hours. After heating up to roomtemperature, water is added, the mixture is extracted with methylenechloride, the organic phase is dried with sodium sulfate and evaporated.The residue is chromatographed on silica gel with methylene chloride andmethanol, thus isolating 265 mg of3-[(2-tert-butyldimethylsilyl)-6-methyl-8α-ergolinyl)]-1,1-diethylurea(40% of theory).

[α]_(D) =+30° (0.5% in chloroform).

EXAMPLE 24

As described in Example 23,1-(tert-butyldimethylsilyl)-2-bromo-8,9-didehydro-6,8-dimethylergolineis used to prepare, with tert-butyllithium, the 2-lithium compound inanhydrous tetrahydrofuran. This solution is stirred for 5 hours at -70°C., then worked up as usual and chromatographed. Yield: 65% of2-(tert-butyldimethylsilyl)-8,9-didehydro-6,8-dimethylergoline.

[α]_(D) =-152° (0.5% in chloroform).

The following 2-silyl compounds are produced in the same way:

3-[2-(tert-butyldimethylsilyl)-6-methyl-8α-ergolinyl]-1,1-diethylthiourea,

3-[2-(tert-butyldimethylsilyl)-9,10-didehydro-6-methyl-8α-ergolinyl]-1,1-diethylurea,yield: 31%; [α]_(D) =+305° (0.5% in chloroform),

8,9-didehydro-6,8-dimethyl-2-trimethylsilylergoline, yield: 60%, [α]_(D)=-177° (0.5% in chloroform),

1,1-diethyl-3-(6-methyl-2-trimethylsilyl-8α-ergolinyl)urea, yield: 59%;[α]_(D) =+30° (0.5% in chloroform),

3-(9,10-didehydro-6-methyl-2-trimethylsilyl-8α-ergolinyl)-1,1-diethylurea,yield: 37%; [α]_(D) =317° (0.5% in chloroform),

3-(6-n-propyl-2-trimethylsilyl-8α-ergolinyl)-1,1-diethylurea,

3-(2-tert-butyldimethylsilyl)-6-methyl-8β-ergolinyl)-1,1-diethylurea.

EXAMPLE 25

At room temperature under argon, 7 ml of ethyl formate and 3.6 ml (44mmol) of ethanedithiol are added in succession to a solution of 6.8 g of1,1-diethyl-3-(6-methyl-8α-ergolinyl)urea in 200 ml of chloroform.Thereafter 8.8 ml (80 mmol) of titanium(IV) chloride dissolved in 100 mlof chloroform is added gradually dropwise to the mixture. The latter isstirred for 20 hours at room temperature. Although the starting materialis not as yet entirely converted at this point in time, the reactionmixture is worked up to avoid further formation of the disubstitutedcompound. For this purpose, the reaction mixture is cooled in an icebath and combined, in sequence, dropwise with 50 ml of methanol and 40ml of water. The mixture is then made alkaline with 25% ammonia solutionand extracted with methylene chloride. The organic phases are washedwith water and dried over magnesium sulfate. The evaporated residue iscrystallized in boiling heat from methanol/ethyl acetate, thus obtaining3.8 g of1,1-diethyl-3-[2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]urea (42%yield).

[α]_(D) =+29° (0.5% in CH₃ OH).

EXAMPLE 26

7.5 ml of a Raney nickel suspension is washed four times withrespectively 30 ml of methanol. Then 15 ml of methanol and thereafter asolution of 670 mg (1.5 mmol) of1,1-diethyl-3-[2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]urea in 15ml of methanol are added thereto. The mixture is agitated for 3 hours atroom temperature and once again 7.5 ml of a Raney nickel suspension isadded which has been washed, as above, previously four times withrespectively 30 ml of methanol. After another 2 hours of agitation atroom temperature, the catalyst is filtered off over a silica gel columnand thoroughly washed with methanol. The filtrate is evaporated and theresidue is crystallized from methanol/ethyl acetate, thus obtaining 170mg of 1,1-diethyl-3-(2,6-dimethyl-8α-ergolinyl)urea (32% yield).

[α]_(D) =+12° (0.5% in CHCl₃).

EXAMPLE 27

2.05 g (5 mmol) of1,1-diethyl-3-[2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]urea isdissolved under argon in 46 ml of chloroform. Then 3.5 g of silica geland, under vigorous agitation, dropwise 3.5 ml of water are added.During a time period of 30 minutes, a solution of 1.18 ml of sulfurylchloride in 30 ml of chloroform is added drop by drop. After stirringfor 3 hours at room temperature, 7.5 g of potassium carbonate is addedand the mixture is vigorously stirred for 20 minutes. The precipitate isfiltered off and washed with chloroform. The precipitate is moistenedwith ethanol and introduced into 300 ml of saturated sodium chloridesolution which is then repeatedly extracted with chloroform. Thechloroform extracts and the chloroform filtrate are jointly dried overmagnesium sulfate and evaporated. The subsequent crystallization isperformed from ethyl acetate, thus isolating 0.93 g of1,1-diethyl-3-(6-methyl-2-formyl-8α-ergolinyl)urea (54% yield).

[α]_(D) =+78° (0.5% in pyridine).

EXAMPLE 28

Under argon, 320 mg (8 mmol) of lithium aluminum hydride is suspended in20 ml of absolute, freshly distilled tetrahydrofuran. At roomtemperature, a solution of 1.40 g (4 mmol) of1,1-diethyl-3-(6-methyl-2-formyl-8α-ergolinyl)urea in 40 ml of freshlydistilled, absolute tetrahydrofuran is added dropwise. Then the mixtureis stirred for 11/4 hours at room temperature. The batch is then cooledin an ice bath and combined with 20 ml of 1N hydrochloric acid. To thismixture is added 20 ml of 2N tartaric acid and the batch is layered overthe ethyl acetate. For neutralization, 80 ml of 1N ammonia solution isadded dropwise. The ethyl acetate phase is separated, and the aqueousphase is reextracted with ethyl acetate. The combined ethyl acetatephases are dried over sodium sulfate. The concentrated crude product ischromatographed on silica gel with methylene chloride/methanol 95:5under pressure. The crude product (1.09 g) is crystallized from ethylacetate, thus obtaining 0.94 g of1,1-diethyl-3-(6-methyl-2-hydroxymethyl-8α-ergolinyl)urea (65% yield).

[α]_(D) =+38° (0.5% in pyridine).

EXAMPLE 29

Under argon, 11.5 g (0.03 mol) of3-(9,10-didehydro-6-methyl-8α-ergolinyl)-1,1-diethylurea is dissolved in300 ml of chloroform. At room temperature, 105 ml of ethyl formate and5.4 ml of ethanedithiol are added in succession. Then 13.2 ml oftitanium(IV) chloride in 150 ml of chloroform is added dropwise. Themixture is agitated for 3 days at room temperature. To work up themixture, it is cooled in an ice bath and 75 ml of methanol and 600 ml ofwater are added in sequence dropwise to this mixture. The solution isrendered alkaline with 60 ml of 25% ammonia solution and extracted withmethylene chloride. The organic phases are washed with water and driedover magnesium sulfate. The concentrated residue is chromatographedunder pressure on silica gel with ethyl acetate/methanol 95:5, thusisolating 1.7 g of3-[9,10-didehydro-2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]-1,1-diethylurea(12% yield).

EXAMPLE 30

Under argon, 1.10 g (2.5 mmol) of3-[9,10-didehydro-2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]-1,1-diethylureais dissolved in 25 ml of chloroform and combined with 1.9 g of silicagel of a particle size of 0.063-0.2 mm. Under vigorous agitation, 2 mlof distilled water is added dropwise. Subsequently, within a time periodof 15 minutes, a solution of 0.5 ml (0.6 mmol) of sulfuryl chloride in13 ml of chloroform is added dropwise and the mixture is stirred for 2hours at room temperature. For working-up purposes, 3 g of potassiumcarbonate is added and the mixture is vigorously agitated for 20minutes. The precipitate is filtered off and washed with methylenechloride. The precipitate is moistened with ethanol and made into aslurry with 250 ml of saturated sodium chloride solution. This mixtureis repeatedly extracted with methylene chloride. The extracts are driedtogether with the methylene chloride filtrate over magnesium sulfate andconcentrated. The crude product is chromatographed under pressure onsilica gel with a chloroform/methanol mixture and the main fraction of448 mg is recrystallized from diisopropyl ether, thus obtaining 225 mgof 3-(9,10-didehydro-2-formyl-6-methyl-8α-ergolinyl)-1,1-diethylurea(25% yield).

[α]_(D) =+398° (0.5% in CHCl₃).

EXAMPLE 31

Under argon, a solution of 244 mg (0.67 mmol) of3-(9,10-didehydro-2-formyl-6-methyl-8α-ergolinyl)-1,1-diethylurea in 25ml of absolute, freshly distilled tetrahydrofuran is added dropwise to asuspension of 52 mg (1.45 mmol) of lithium aluminum hydride in 3 ml ofabsolute, freshly distilled tetrahydrofuran at room temperature. Themixture is stirred for one hour at room temperature. The batch is cooledin an ice bath and combined in succession with 3 ml of 1N hydrochloricacid and 3 ml of 2N tartaric acid. The mixture is layered over withethyl acetate and made alkaline with 12 ml of 1N ammonia solution. Theethyl acetate phase is separated and the aqueous phase is additionallyextracted twice with ethyl acetate. The combined ethyl acetate phasesare dried over sodium sulfate and concentrated. The product iscrystallized from ethyl acetate, yielding 161 mg of3-(9,10-didehydro-2-hydroxymethyl-6-methyl-8α-ergolinyl)-1,1-diethylurea(65% yield).

[α]_(D) =+328° (0.5% in pyridine).

EXAMPLE 32

Analogously to Example 6, the corresponding lithium compound is obtainedfrom3-(2-bromo-1.tert-butoxydimethylsilyl-6-methyl-8α-ergolinyl)-1,1-diethylthioureawith tert-butyllithium, and from this compound, with dimethyl disulfide,the 1,1-diethyl-3-(6-methyl-2-methylthio-8α-ergolinyl)thiourea isobtained.

Yield: 38%; [α]_(D) =+54° (0.5% in chloroform).

EXAMPLE 33

Under argon, 0.3 ml (1.5 mmol) of distilled hexamethyldisilazane isadded to 4 ml of absolute, freshly distilled toluene, and the mixture iscooled to 0° C. Then 0.85 ml (1.4 mmol) of 15% butyllithium/hexane isadded dropwise and the mixture is stirred for 15 minutes at 0° C. Tothis mixture is added 531 mg (1 mmol) of3-[2-bromo-1-(tert-butyldimethylsilyl)-9,10-didehydro-6-methyl-8α-ergolinyl]-1,1-diethylureain 50 ml of absolute, freshly distilled toluene and agitation iscontinued for another 15 minutes at 0° C. After adding 1 ml of distilledtetramethylethylenediamine, the batch is cooled to -90° C. At thistemperature, 5 ml (7 mmol) of 1.4M tert-butyllithium is added and themixture is agitated for 2 minutes before 0.6 ml (5.4 mmol) of the methylester of trifluoromethanesulfonic acid is added thereto. After 11/2hours of agitation at -70° C., water is added to work up the reactionmixture. Extraction is performed with ethyl acetate. The organic phasesare washed with saturated sodium bicarbonate solution and water. Thecombined ethyl acetate phases are dried over sodium sulfate andconcentrated. Crystallization from methanol produces 128 mg of3-[1-(tert-butyldimethylsilyl)-9,10-didehydro-2,6-dimethyl-8α-ergolinyl]-1,1-diethylurea(27% yield).

[α]_(D) =+252.1° (0.5% in CHCl₃).

EXAMPLE 34

Under argon, 183 mg (0.39 mmol) of3-[1-(tertbutyldimethylsilyl)-9,10-didehydro-2,6-dimethyl-8α-ergolinyl]-1,1-diethylureais dissolved in 5 ml of methanol with addition of 2 ml oftetrahydrofuran and stirred with 1 ml of 14N potassium hydroxidesolution at room temperature for 17 hours. To work up the mixture, it isdiluted with saturated sodium chloride solution and extracted withmethylene chloride. The methylene chloride extracts are washed withsaturated sodium chloride solution and water and dried over sodiumsulfate. The crude product of 128 mg is chromatographed and crystallizedas the tartrate, thus obtaining 94 mg (67% of theory) of3-(9,10-didehydro-2,6-dimethyl-8α-ergolinyl)-1,1-diethylurea.

[α]_(D) =+222° (0.1% in pyridine).

Analogously, by replacing the trifluorosulfonic acid methyl ester by theethyl ester,3-(9,10-didehydro-2-ethyl-6-methyl-8α-ergolinyl)-1,1-diethylurea isobtained and crystallized as the tartrate. Yield: 21%;

[α]_(D) =+195° (0.1% in pyridine).

The following compounds are obtained by replacing thetrifluoromethanesulfonic acid ester by the p-toluenesulfonic acid thioester (ethyl, n-propyl and isopropyl):

3-(9,10-didehydro-2-ethylthio-6-methyl-8α-ergolinyl)-1,1-diethylurea.Yield: 26%; [α]_(D) =+299° (0.5% in chloroform);

3-(9,10-didehydro-6-methyl-2-n-propyl-8α-ergolinyl)-1,1-diethylurea.Yield: 38%; [α]_(D) =284° (0.5% in chloroform);

3-(9,10-didehydro-6-methyl-2-isopropyl-8α-ergolinyl)-1,1-diethylurea.Yield: 21%; [α]_(D) =+286° (0.5% in chloroform).

Using as the starting material3-[2-bromo-1-(tert-butyldimethylsilyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea,then, with the ethyl ester of trifluoromethanesulfonic acid,3-(2-ethyl-6-methyl-8α-ergolinyl)-1,1-diethylurea is obtained. Yield:29%;

with the thioethyl ester of p-toluenesulfonic acid,3-(2-ethylthio-6-methyl-8α-ergolinyl)-1,1-diethylurea. Yield: 78%;[α]_(D) =+5° (0.5% in chloroform);

with the thio-n-propyl ester of p-toluenesulfonic acid,1,1-diethyl-3-(6-methyl-2-n-propylthio-8α-ergolinyl)urea. Yield: 75%;[α]_(D) =+4° (0.5% in chloroform);

with the thio-isopropyl ester of p-toluenesulfonic acid,1,1-diethyl-3-(6-methyl-2-isopropylthio-8α-ergolinyl)urea. Yield: 35%;[α]_(D) =+4° (0.5% in chloroform); and

with the phenylcyanate,3-(2-cyano-6-methyl-8α-ergolinyl)-1,1-diethylurea. Yield: 12%; [α]_(D)=0.5% in pyridine).

EXAMPLE 35

1.4 g (3 mmol) of 3-(2-iodo-6-methyl-8α-ergolinyl)-1,1-diethylurea, 37.5mg (0.123 mmol) of tri-o-tolylphosphine, 25.1 mg (0.032 mmol) oftrans-dichloro-bis(tri-o-tolylphosphine) palladium (II) and 1.13 ml (7.8mmol) of vinyltrimethylsilane are dissolved in 7.5 ml oftrimethylformamide and 7.5 ml of triethylamine and, after purging withargon, heated in an autoclave for 3 hours to 100° C. After concentrationof the reaction solution under reduced pressure, the solution is takenup in dichloromethane and washed with saturated sodium chloridesolution. After drying over magnesium sulfate, the organic phase isconcentrated. The crude product yields, after column chromatography oversilica gel with dichloromethane/ethanol 10:1 as the eluent andrecrystallization from ethanol/petroleum ether, 400 mg of3-[6-methyl-2-(trans-2-trimethylsilyl-1-ethenyl)-8α-ergolinyl]-1,1-diethylurea(30.2%), mp 194°-197° C.; [α]_(D) =+89.0° (c=0.225% in pyridine);

and

563 mg of 3-(2-ethenyl-6-methyl-8α-ergolinyl)-1,1-diethylurea (51.2%),mp 145°-150° C.; [α]_(D) =+63.5° (c=0.23% in pyridine).

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. An ergoline substituted in the 2-position of theformula ##STR20## wherein C₈ - - - C₉ and C₉ - - - C₁₀ eachindependently is a CC-single or a C═C-bond, but not a cumulated doublebond, and the substituent in the 8-position is in the α- orβ-configuration where C₈ - - - C₉ is a CC-single bond,R² isSOR,##STR21## or --CH(OH)R wherein R is H or C₁₋₄ -alkyl and n is 2 or 3;COR' OR CSR' wherein R'=OH, OC₁₋₄ -alkyl, benzyl, NH₂ or NHR";CH═CH--CO₂ R" or CH₂ --CH₂ --CO₂ R" wherein R"=C₁₋₄ alkyl, C═C--R'" orHC═CH--R'" wherein R'"=hydrogen, C1-4-alkyl, phenyl, CH₂ OH, CR"₂ OH##STR22## CO₂ R, CH₂ NR"₂ or SiMe₂ R"; C₁₋₃ -alkyl substituted by OH orphenyl; or ##STR23## wherein R" is C₁₋₄ -alkyl, R⁶ is C₁₋₄ -alkyl and R⁸is methyl, NH--CO--NEt₂ or NH--CS--NEt₂, or a physiologically acceptableacid addition salt thereof.
 2. A compound of claim 1 wherein R⁸ isNH--CO--NEt₂.
 3. A compound of claim 2 wherein C₈ - - - C₉ is aC═C-double bond and C₉ - - - C₁₀ is a CC single bond.
 4. A compound ofclaim 2 wherein C₈ - - - C₉ is a CC single bond and C₉ - - - C₁₀ is aC═C double bond.
 5. A compound of claim 1 wherein R⁸ is NH--CS--NEt₂. 6.A compound of claim 5 wherein C₈ - - - C₉ is a C═C-double bond andC₉ - - - C₁₀ is a CC single bond.
 7. A compound of claim 5 whereinC₈ - - - C₉ is a CC single bond and C₉ - - - C₁₀ is a C═C double bond.8. A compound of claim 1 wherein R⁸ is methyl.
 9. A compound of claim 8wherein C₈ - - - C₉ is a C═C double bond and C₉ - - - C₁₀ is a CC singlebond.
 10. A compound of claim 8 wherein C₈ - - - C₉ is a CC single bondand C₉ - - - C₁₀ is a C═C double bond. 11.1,1-Diethyl-(6-methyl-2-ethynyl-8α-ergolinyl)urea, a compound ofclaim
 1. 12. A pharmaceutical composition for treating depressioncomprising an effective amount of a 2-substituted ergolinyl compound ofclaim 1 and a pharmaceutically acceptable carrier.
 13. A method ofachieving neuroleptic effect in a patient comprising administering aneffective amount of an ergolinyl compound of claim
 1. 14. A method oftreating depression in a patient comprising administering to the patientan antidepressantly effective amount of an ergolinyl compound of claim1.